In March 2012 Image Comics published the first issue of Saga, an ongoing series conceived by writer Brian K. Vaughan.[9] Staples was introduced to Vaughan by their mutual friend, writer Steve Niles, with whom Staples worked on Mystery Society.[10] Vaughan, who had not met Staples in person until just before their panel at the 2011 San Diego Comic-Con, explained his selection of Staples by describing his reaction upon first seeing her work, saying, "Her artwork is incredible. [It] doesn't look like anyone else. She is very unique. When I opened up this file I was like, 'This is going to work!'" Staples is co-owner of Saga,[11] who designed the cast[12] and all the ships and alien races in the story. She also provides painted covers, and hand-letters the narration (using her own handwriting), which is the final work she does after finishing the artwork on a page.[10][13][14]

In 2015, Staples and writer Mark Waid became the creative team for the opening three-issue story arc of Archie Comics' relaunched Archie, in celebration of the character's 75th anniversary. Staples, who had previously provided variant covers for the publisher, contributed her distinctive drawing style, rather than Archie's house style, and designed "a new look and an edgier tone" for the Archie comicbook, whose storylines will portray the character in darker, more complicated situations, though not necessarily for a strictly adult audience.[15][16]

At the beginning of her career, Staples would scan traditional drawings in and edit them in photoshop later.[1] Staples began creating her artwork entirely digitally several years before she began work on Saga, though her process for that series is different from previous ones, for which she characterizes it as "one intense, ongoing experiment." She begins with thumbnails, roughly drawn on printed paper templates. During this stage Staples gives copious thought to the layouts and staging, making it, in her words, the most important part of the process. After scanning the thumbnails, she enlarges them and uses them as rudimentary pencils, and "inks" over them in Manga Studio. She has said that her art distributor is "perpetually disappointed in her," as fans would pay steep prices for inks and pencils.[1]

One of the advantages Staples sees in working digitally is the ability to dispense with tight pencils in favor of making corrections in an ad hoc manner, as she finds that penciling in great detail, and re-drawing such artwork a second time in ink, to be boring. In Saga, Staples inks only the figures in pen-and-ink, using a lot of self-shot photo references to finalize the poses, which she does not use in the thumbnail stage. She then imports the art into Photoshop, which she uses to paint the backgrounds entirely in colour,[17] to achieve a look inspired by video games and Japanese animation.[12] At the 2012 Image Expo, Staples described the process by which she produces the art as harkening back to animation cels, in which emphasis is placed on figures and backgrounds.[18] The process, according to Staples, can be time-consuming, depending on the complexity of the environment.

For outdoor environments, she begins by selecting a colour palette and initially blocking in the shapes roughly. She subsequently colours the figures, using flat colours both to make the process quicker and because she feels that painted figures in comics can often look "stiff" and difficult for the reader to "read" quickly. For pages that feature narration by the character Hazel, Staples writes the text using her own handwriting.[17] Vaughan has stated that Staples's style has influenced the direction of the story.[11] The organic forms of most of the series' technology, for example, such as the main characters' wooden rocket ship, is derived from Staples's dislike of drawing mechanical objects.[12] To design the series' various planetary settings, Staples looks to the real world for inspiration and then exaggerates some elements of them. Some rooms on the planet Cleave, for example, were inspired by Cambodian architecture.[14]

Staples's work on Saga received wide acclaim from numerous reviewers,[19] with Ain't it Cool News characterizing it as "glorious",[20] and P.S. Hayes of Geeks of Doom praising her art as "amazing", saying, "From the gorgeous painted cover all the way through the last page, she delivers in every way that’s artistically possible. It’s got to be tough to be handed a script like this one and try and figure out what to do, but she handles it beautifully. Everything looks like it belongs in the universe. Her backgrounds are elaborate, yet never distracting or too busy and they never take focus off the main characters."[21]

Alex Zalben of MTV Geek predicted readers would "fall head over heels in love" with it,[22] and Greg McElhatton of Comic Book Resources positively compared it to that of Leinil Francis Yu, specifically her use of delicate lines to frame characters with large, bold figures, and her mixture of the familiar and the foreign together in her character designs to create a visually cohesive universe.[23] AICN singled out Staples's handling of grand, sweeping space shots and other genre trappings, as well as her mastery of facial expressions, which AICN felt was perfectly suited to Vaughan's subtle dialogue.[20]

In 2015, Staples was voted the #1 female comic book artist of all-time by readers of Comic Book Resources.[24]